Phase 3 APPLY-PNH Extension Data Show Sustained Benefit of Iptacopan (Fabhalta) for PNH


Results showed treatment with iptacopan through 48 weeks caused hemoglobin-level increases, blood transfusion avoidance, and reductions in patient-reported fatigue.

Antonio Risitano, MD, PhD | Credit: European School of Haematology

Antonio Risitano, MD, PhD

Credit: European School of Haematology

Novartis has announced results from the extension period of the phase 3 APPLY-PNH trial for iptacopan (Fabhalta) in adults with paroxysmal nocturnal hemoglobinuria (PNH) who had residual anemia (hemoglobin <10 g/dL) despite previous anti-C5 therapy.

Announced on December 11, 2023, data showed twice daily treatment with iptacopan 200 mg for 48 weeks enabled sustained hemoglobin-level increases to > 12 g/dL, blood transfusion avoidance, and reduced patient-reported fatigue, with comparable benefits observed among patients who switched from anti-C5 therapy to iptacopan in the extension period.1

“The new APPLY-PNH data are an expansion of the robust outcomes we saw in the randomized phase and demonstrate that patients with PNH who took Fabhalta experienced meaningful hemoglobin improvement over the longer term – nearly a year,” said Antonio Risitano, MD, PhD, president of the International PNH Interest Group and head of the Hematology and Hematopoietic Transplant Unit and Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati in Italy.1 “Additionally, the new data confirm that these benefits may occur within weeks after switching from anti-C5s. The APPLY-PNH findings continue to confirm Fabhalta as a promising therapeutic option for people living with PNH.”

The extension data comes just days after the US Food and Drug Administration (FDA) approved iptacopan for the treatment of adults with PNH, making it the first FDA-approved Factor B inhibitor of the immune system’s complement pathway.2 According to the release, data will be presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.1

Along with its indication for PNH, iptacopan is currently in development for a range of other complement-mediated diseases including immunoglobulin A nephropathy, C3 glomerulopathy, immune complex membranoproliferative glomerulonephritis, and atypical hemolytic uremic syndrome. Of note, Novartis announced positive phase 3 data for iptacopan in C3 glomerulopathy on December 11, 2023, with results from APPEAR-C3G showing clinically meaningful and statistically significant proteinuria reduction.2,3

A phase 3, randomized, multinational, multicenter, active-comparator controlled, open-label trial, APPLY-PNH assessed the efficacy and safety of twice-daily oral iptacopan monotherapy 200 mg and sought to demonstrate its superiority compared to anti-C5 antibody treatments eculizumab and ravulizumab in adult patients with residual anemia despite a prior stable regimen of anti-C5 treatment.1

For inclusion, patients were required to be ≥ 18 years of age, diagnosed with PNH, on a stable regimen of anti-C5 antibody treatment with either eculizumab or ravulizumab for at least 6 months prior to randomization, have mean hemoglobin level <10 g/dL, and be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. In total, the trial enrolled 97 patients who were randomized in an 8:5 ratio to treatment with twice-daily oral iptacopan monotherapy, or intravenous anti-C5 therapies.2

Patients completing the 24-week randomized treatment period of APPLY-PNH could elect to enter the extension, continuing iptacopan (n = 61) or switching from anti-C5s to iptacopan (n = 34) through week 48.1

Among participants who continued with iptacopan, investigators noted outcomes achieved in the randomized period were sustained at 48 weeks. Mean hemoglobin level continued to be near-normal (12.2 g/dL), 91.9% of patients remained free of transfusions from week 2 through week 48, and improvements in patient-reported fatigue were observed with an adjusted mean 9.80-point increase in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score from baseline.1

Among participants who switched from anti-C5 to iptacopan, similar benefits emerged: mean hemoglobin levels increased from 9.1 g/dL at 24 weeks to 12.1 g/dL at 48 weeks, transfusion avoidance was achieved for 94.1% of participants from week 26 through week 48, and improvements in patient-reported fatigue were observed after switching to iptacopan with an adjusted mean 10.79-point increase in FACIT-F score from baseline between week 48 and week 24.1

According to the release, iptacopan had a similar safety profile at 48 weeks compared to 24 weeks. The most frequently reported treatment-emergent adverse events in the iptacopan arm were COVID-19 (29.0%), headache (19.4%), and diarrhea (16.1%). Throughout the full 48 weeks on iptacopan, 9.7% of patients experienced any severe treatment-emergent adverse event and 14.5% experienced any serious treatment-emergent adverse event, none of which were considered to be related to iptacopan treatment.1

“Coming on the heels of Fabhalta’s recent approval in PNH, these extended data from the APPLY-PNH phase III trial reinforce Fabhalta’s utility as an important new oral monotherapy for people living with PNH,” said David Soergel, MD, global head of the cardiovascular, renal, and metabolism development unit at Novartis.1 “We are eager to bring this novel treatment to even more people living with rare complement-driven disorders as we pursue several additional indications for Fabhalta.”


  1. Novartis. Novartis presents new 48-week results from Phase III APPLY-PNH trial showing sustained efficacy and long-term safety of Fabhalta® (iptacopan) in adults with paroxysmal nocturnal hemoglobinuria (PNH). News. December 11, 2023. Accessed December 11, 2023.
  2. Brooks, A. FDA Approves Iptacopan (Fabhalta) for Paroxysmal Nocturnal Hemoglobinuria. HCPLive. December 6, 2023. Accessed December 11, 2023.
  3. Novartis. Novartis investigational iptacopan Phase III study demonstrates clinically meaningful and statistically significant proteinuria reduction in patients with C3 glomerulopathy (C3G). News. December 11, 2023. Accessed December 11, 2023.
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